LINE-1 Methylation Level and Patient Prognosis in a Database of 208 Hepatocellular Carcinomas
LINE-1 Methylation Level and Patient Prognosis in a Database of 208 Hepatocellular Carcinomas
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DOI：
10.1245/s10434-014-4134-3
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发表时间：
2015-04-01
影响因子：
3.7
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
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作者：
Harada, Kazuto;Baba, Yoshifumi;Baba, Hideo
长散布核苷酸元件-1（LINE-1）甲基化的水平已被认为是全局DNA甲基化的替代标记。以前，我们证明LINE-1低甲基化可能有助于通过食管鳞状细胞癌中癌基因（如细胞周期蛋白依赖性激酶6（CDK 6））的基因组获得获得侵袭性肿瘤行为。采用焦磷酸测序法检测了208例肝细胞癌（HCC）手术切除标本中LINE-1甲基化水平，并分析了LINE-1甲基化水平对HCC预后的影响。中位数64.6;标准差（SD）13.6;范围21.5-99.1;四分位数间距62.9-66.6。单变量考克斯回归分析显示，低甲基化水平组的癌症复发率显著高于高甲基化水平组（风险比1.58; 95% CI 1.05-2.47; p = 0.028）。有趣的是，LINE-1低甲基化对患者结局的影响被肝炎病毒感染改变（相互作用的p = 0.023）; LINE-1低甲基化与无肝炎病毒感染患者的较高癌症复发率相关（对数秩p = 0.0047）。CDK 6信使RNA表达水平与LINE-1甲基化水平呈负相关（p = 0.0075; R = -0.37）。通过LINE-1水平测量的全基因组DNA低甲基化可能与HCC患者的无病生存率低相关，表明LINE-1甲基化水平作为生物标志物用于识别将经历不利临床结果的患者的潜在作用。
The level of long interspersed nucleotide element-1 (LINE-1) methylation has become regarded as a surrogate marker of global DNA methylation. Previously, we demonstrated that LINE-1 hypomethylation might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as cyclin-dependent kinase 6 (CDK6) in esophageal squamous cell carcinoma. However, the relationship between LINE-1 hypomethylation and clinical outcome in hepatocellular carcinoma (HCC) remains unclear.LINE-1 methylation level in 208 samples of curatively resected HCCs was measured by pyrosequencing assay, and the prognostic value of LINE-1 methylation level in HCC was examined.LINE-1 methylation levels in the 208 HCC patients investigated were distributed as follows: mean 64.7; median 64.6; standard deviation (SD) 13.6; range 21.5-99.1; interquartile range 62.9-66.6. Univariate Cox regression analysis revealed a significantly higher cancer recurrence rate in the low-methylation-level group than in the high-methylation-level group (hazard ratio 1.58; 95 % CI 1.05-2.47; p = 0.028). Interestingly, the influence of LINE-1 hypomethylation on patient outcome was modified by hepatitis virus infection (p of interaction = 0.023); LINE-1 hypomethylation was associated with a higher cancer recurrence rate in patients without hepatitis virus infection (log-rank p = 0.0047). CDK6 messenger RNA expression levels were inversely associated with LINE-1 methylation levels (p = 0.0075; R = -0.37).Genome-wide DNA hypomethylation, as measured by LINE-1 levels, might be associated with poor disease-free survival in HCC patients, suggesting a potential role for LINE-1 methylation level as a biomarker for identifying patients who will experience an unfavorable clinical outcome.